The invention is directed to compositions having an oil phase that contains pharmaceutically active ingredients that are charged amphiphilic or water soluble. The compositions generally comprise tocol-soluble ion pairs in a tocol-based oil of a multiphasic system or a precursor of such a system. The compositions of the invention can be in the form of an emulsion, liquid crystalline gel, self-emulsifying drug delivery system, or a liposomal or niosomal dispersion for oral or parenteral administration, which term is meant to include, for instance, intravenous, subcutaneous, intraperitoneal, intramuscular, pulmonary, intranasal, and topical administration such as transdermal and ocular. Emulsions or microemulsions and self-emulsifying drug delivery systems are the preferred form of the compositions of the present invention.
Emulsions, and emulsification as a composition and method of administration of pharmaceuticals, have a long history in the medical arts. A recent advance was the use of xcex1-tocopherol or other tocopherols, tocotrienols or derivatives thereof as a solvent to dissolve certain drugs at high enough concentrations to be therapeutically useful. TPGS (60 -tocopherol polyethyleneglycol 1000 succinate) for administration of a therapeutic was claimed by Biogal (U.S. Pat. No. 5,583,105) following disclosure in trade publications of the utility of TPGS as a bioavailability enhancer for drug delivery (Sokol, et al. The Lancet 338:212-215, 1991). Vitamin E and tocopherol acetates and succinates, including TPGS, were recently found useful in pharmaceutical formulations as solubilizers and co-solvents for the administration of medicaments (Dumex WO/95,31217 and Liposome Company, U.S. Pat. No. 5,041,278). Other patents disclose that tocopherols are excellent solvents for the peptide cyclosporin (Klokkers WO 95/11039), and for certain steroids (Peat, U.S. Pat. No. 4,439,432). Stillman (U.S. Pat. No. 4,551,332), and Hermes Pharma (EP 019817) described composition in which steroids and antibiotics, or ubiquinones, respectively, were co-solubilized in Vitamin E as pharmaceutical formulations.
Subsequent disclosures by Sonus Pharmaceuticals (WO 98/30205); Sherman (WO 97/22358; WO 98/30204) and Danbiosyst (WO 97/03651; WO 99/04787) expanded this new appreciation of tocopherols and tocotrienols as a solvent for delivery of hydrophobic medicaments, particularly when combined with TPGS, phospholipids, and certain co-solvents and emulsifiers.
The benefits of emulsions are several. In general, emulsification can lead to reduced toxicity when compared to aqueous solutions of the drug. Extreme conditions of pH or ionic strength are required to solubilize some drugs in aqueous solutions. Also, sustained release has been observed from emulsions formed as a blood pool or intra-tissue depot, from which the active agent is progressively released with desirable increased efficacy or duration of treatment. In other cases, a high plasma peak concentration (Cmax) can be obtained without undue risk to the patient. Finally, the stability of selected drugs in the oil phase may be improved when compared to aqueous solutions of the same drug. Emulsions in tocopherols, tocotrienols or derivatives thereof have the added advantage that the emulsion itself may be therapeutic for certain conditions.
However, only selected lipophilic active agents are highly soluble in tocopherols and tocotrienols. Furthermore, lipophilic agents that are charged tend to remain associated with the water or plasma, where they may be subject to degradation, even while residing in part in the oil phase. Finally, some water-soluble agents or amphiphilic agents that could benefit from the advantages of a tocopherol or tocotrienol formulation are not readily soluble in these oils.
It would thus be desirable to provide pharmaceutical compositions in which a charged amphiphilic or water soluble active agent is partitioned into the tocol oil phase of a multiphasic system.
One approach to improve the oil solubility of such ingredients is to covalently modify the active agent so as to render it more lipophilic. Fatty acid- or lipid-drug conjugates have been disclosed as a means of rendering water-soluble drugs more lipophilic, more readily absorbable through various mucosal membranes, such as the intestinal, corneal and dermal, and for targeting of drugs (NexStar U.S. Pat. Nos. 6,024,977; 5, 827,819; 5, 543,389; 5,543,390; 5,840,674; 5,543,391; 5,256,641; 5,149,794).
Another solution has been to use liposomes, reverse emulsions or water/oil/water multiple emulsions, in which the drug may be contained in an aqueous phase dispersed in the oil matrix or, in the case of liposomes, enclosed within a lipid bilayer. These formulations are particularly valuable for water-loving drugs and macromolecules but may not provide the advantages of solubilizing the drug directly in the oil. In addition there are physical stability considerations of such systems.
The invention comprises a pharmaceutical composition comprising a tocol as a solvent and a tocol-soluble ion pair of two oppositely charged compounds, one of the said compounds being a charged pharmaceutically active agent or a charged precursor of the active agent and the other being an oppositely charged compound capable of forming a tocol-soluble ion pair with the pharmaceutically active compound. In cases of multiply charged pharmaceutically active compounds or precursors of charged pharmaceutically active compounds at least one charge on the active agent is available for ion-pairing. The invention also relates to processes for preparing such compositions.